Thyroid hormone (T3) markedly influences the contractile and electrophysiological function of the heart. Recent results from T3 receptor (TR) knockout (KO) mice indicate that TR alpha KO mice have decreased contractile function and heart rate but TR beta KO mice have normal cardiac function. TR alpha 1 is the predominant TR isoform (TRI) in the heart and the TR alpha KO cardiac phenotype could therefore result from quantitative and overlapping or unique qualitative TR alpha 1 effects. In Aim I we will explore the quantitative and/or qualitative nature of the TR isoform effects on the heart in rescue type of experiments using viral vectors, crosses of TRI KO mice with TRI transgenic mice and TR alpha and TR beta gene promoter knock in mice expressing tagged TR alpha 1 or TR beta 1 in cardiac myocytes. Contractile function and gene expression profiles using conventional mRNA quantitation and DNA microarrays will be determined. In addition we will use TR alpha exon 3 LoxP floxed mice, which allow for myocyte specific inducible deletion of TR alpha, to determine developmental influences and effects of other organs on cardiac function. We recently generated these mice. In Aim II we will determine in wild type mice with pressure overload induced heart failure (HF) exhibiting decreased TR and T3 levels if the diminished contractile phenotype can be rescued using viral vector or transgenic animal based TR alpha 1 or TR beta 1 substitution in combination with TR ligands. With adequate rescue by TR beta 1 novel T3 analogues, with preferred TR beta 1 binding like GC1, can be used which have markedly diminished effects on heart rate compare to T3, potentially allowing for contractile rescue without unwanted electrophysiological effects. These studies will provide new insights into a specific type of non-thyroidal illness syndrome resulting from HF which presents a very significant medical problem. In Aim III the basis for T3 mediated increased in heart rate will be explored by identifying T3 responsive pacemaker ion channels in the sinus node. In addition the mechanisms underlying hyperthyroidism induced atrial fibrillation will be determined.